succimer and Lead-Poisoning--Nervous-System

This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.

Topics: Arsenic Poisoning; Chelating Agents; Edetic Acid; Humans; Lead Poisoning, Nervous System; Mercury Poisoning, Nervous System; Monensin; Succimer; Unithiol

Topics: Aged, 80 and over; Chelating Agents; Diagnosis, Differential; Female; Humans; Lead Poisoning, Nervous System; Muscle Weakness; Neurologic Examination; Peripheral Nervous System Diseases; Succimer

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Topics: Animals; Antioxidants; Apoptosis; Behavior, Animal; Biogenic Amines; Calcium; Captopril; Chelating Agents; Cytochromes c; Disease Models, Animal; DNA Damage; Drug Therapy, Combination; Exploratory Behavior; Lead Poisoning, Nervous System; Learning; Male; Membrane Potential, Mitochondrial; Memory; Mitochondria; Motor Activity; Nerve Degeneration; Neurons; Nitric Oxide; Organometallic Compounds; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Succimer

The clinical presentation of lead intoxication may vary widely and in the absence of a high clinical index of suspicion, the diagnosis may be missed. The effects of lead on mitochondrial oxidative phosphorylation and its interaction with calcium-mediated processes explain the heterogenous presentation. In this case report, the diagnosis was finally made when bilateral wrist drop developed on top of abdominal cramps and anemia. Before, ascites raised the suspicion of a tumor. Therefore, each element of the triad of unexplained anemia, abdominal cramps, and bilateral wrist (or foot) drop should lead any physician to consider the diagnosis of lead intoxication. This case also illustrates the importance of a careful and meticulous social history in patient management.

Topics: Abdominal Neoplasms; Chelating Agents; Diagnosis, Differential; Female; Flowers; Hobbies; Humans; Lead Poisoning; Lead Poisoning, Nervous System; Middle Aged; Protoporphyrins; Succimer; Treatment Outcome

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of

Topics: Animals; Brain; Chelating Agents; Chelation Therapy; Disease Models, Animal; Environmental Exposure; Humans; Lead; Lead Poisoning, Nervous System; Macaca mulatta; Male; Succimer